An Enhanced Effect of Arginine Vasopressin in Bradykinin B 2 Receptor Null Mutant Mice

Abstract

Abstract —Under water restriction, arginine vasopressin (AVP) is released and promotes water reabsorption in the distal nephron, mainly through AVP V 2 -receptors. It has been proposed that renal kinins counteract the hydro-osmotic effect of AVP. We hypothesized that kinins acting through B 2 receptors antagonize the urinary concentrating effect of AVP. To test this, bradykinin B 2 receptor knockout mice (B 2 -KO) and 129/SvEv mice (controls) were placed in metabolic cages and urine collected for 24 hours (water ad libitum). After that, urine was again collected from the same mice during 24 hours of water restriction. Urinary volume (UV), urinary osmolarity (UOsm), and urinary Na + (U Na V) and K + (U K V) excretion were determined. On water restriction, UV in controls decreased by ≈25%, whereas in B 2 -KO mice there was almost a 60% drop in urinary output ( P =0.001 versus controls). In the controls, water restriction increased UOsm by 347 mOsm/kg H 2 O, ≈14% above baseline (NS), whereas in knockout mice the increase was 3 times that seen in the controls: >1000 mOsm/kg H 2 O ( P =0.001 versus controls). Compared with normohydration, U Na V and U K V in the water-restricted state increased more in controls than in B 2 -KO mice. This difference in electrolyte excretion could be explained by greater dehydration in the controls (dehydration natriuresis). In a second protocol, we tried to mimic the effect of endogenous AVP by exogenous administration of an AVP V 2 -receptor agonist, desmopressin (DDAVP). To suppress endogenous AVP levels before DDAVP administration, mice were volume-overloaded with dextrose and alcohol. UOsm was 685±125 and 561±58 mOsm/kg H 2 O in water-loaded controls and B 2 -KO mice, respectively. After DDAVP was injected subcutaneously at a dose of 1 μg/kg, UOsm increased to 1175±86 mOsm/kg H 2 O ( Δ +490 mOsm) in the controls and 2347±518 mOsm/kg H 2 O ( Δ +1786 mOsm) in B 2 -KO mice ( P <0.05 versus controls). We concluded that water restriction or exogenous administration of an AVP V 2 -receptor agonist has a greater urinary concentrating effect in B 2 -KO mice than in controls, suggesting that endogenous kinins acting through B 2 receptors oppose the antidiuretic effect of AVP in vivo.